a. Field of Invention
This invention relates to a method and to compositions for reducing or treating gastrointestinal side effects caused by antiinflammatory agents. More particularly, this invention relates to the finding that the adminstration of certain prostaglandin derivatives to a mammal inhibits and alleviates the gastrointestinal side effects, for example, ulceration, gastrointestinal bleeding, epigastric distress, diarrhea, melena and the like, associated with antiinflammatory drug therapy.
B. Background of the Invention
Antiinflammatory agents, for example, indomethacin, phenylbutazone, oxyphenylbutazone, aspirin and the like, are useful for the treatment of arthritic and rheumatic diseases. However, the use of these agents is associated with a rather high incidence of side effects, the most serious being those related to gastrointestinal reactions. In fact, it has been stated that one of the most common reasons for discontinuing therapy with such agents is the development of a peptic ulcer.
Realizing the serious drawback of this form of therapy, Y. H. Lee, et al., Arch. Int. Pharmacodyn. Ther., 192, 370 (1971), administered various known antiulcer compounds to rats treated with a gastric ulcer-producing dose of indomethacin to evaluate the possible utility of serveral types of antiulcer compounds in reducing the ulcerogenic activity of indomethacin. Some of the compounds evaluated, for example propantheline bromide, proved to be effective but only when administered at does much higher than their usual therapeutic dose.
In a related development it has been suggested that certain prostaglandin derivatives may be of value for the treatment of peptic ulcers. This suggestion is based on the finding that prostaglandin E.sub.1 and several of its analogs inhibit gastric acid secretion; for example, see W. Lippmann, Ann. N.Y. Acad. Sci., 180, 332 (1971).
In view of the foregoing the finding of the present disclosure is surprising and interesting indeed. Namely, it has been found that the prostaglandin derivatives of the present disclosure inhibit ulcer formation and alleviate the symptoms concerned therewith at doeses substantially less than those required for the inhibition of the basal secretion of gastric acid.
This finding is even more surprising in light of the finding that similar inhibition and treatment of aspirin-induced ulcers is achieved at doses of prostaglandins substantially more than required for the inhibition of basal secretion of gastric acid.
Furthermore, other gastrointestinal disturbances associated with the antiinflammatory agents as well as the diarrheal effect associated with larger doses of the natural prostaglandins, for example, prostaglandin E.sub.1 [J.J. Misiewicz, et al., Lancet, 1, 648 (1969)], are antagonized and minimized.
It is worth noting at this point that the natural PGE.sub.1, PGE.sub.2, PGF.sub.1.sub..alpha. and PGF.sub.2.sub..alpha. do have the disadvantage of being relatively unstable, see T.O. Oesterling, et al., J. Pharm. Sci., 61, 1861 (1972). For example, it is well known that the 11-hydroxy group of PGE.sub.1 and PGE.sub.2 participates readily in dehydration reactions under both basic and acidic conditions, see S. Bergstrom et. al., J. Biol. Chem. 238, 3555 (1963), E.J. Corey et al., J. Amer. Chem. Soc., 90, 3245 (1968), J.E. Pike et al., J. Org. Chem. 34, 3552 (1969) and "The Prostaglandins, Progress in Research," S.M.M. Karim, Ed., Wiley-Interscience, New York, 1972, p. 10.
As realized by those skilled in the art this inherent disadvantage of the natural compounds must always be taken in account when considering the practical aspects of preparation, formulation or storage of these compounds. In contrast, the compounds of formula 1 are free from this disadvantage.